Recent large scale genomic and transcriptome analyses of patient glioblastoma cells (GBM) indicate that the intratumoral heterogeneity involving the genetic and epigenetic aberrations of glioblastoma stem-like cells (GSCs) orchestrate human GBM malignancy, recurrence, and chemo- radiation resistance. However, effective strategies to neutralize GSCs remain elusive due to difficulty in GSC-targeted drug delivery and lack of effective genetic targets. Building on our expertise in therapeutic stem cells (FDA approved human neural stem cells for clinical trials / as well as mesenchymal stem cells / hMSCs), here we propose novel therapies targeting the recently identified core set of up-regulated neurodevelopmental transcriptional factors (TFs) - POU3F2, SOX2, SALL2, and OLIG2 - which collectively engender the tumor propagating GSC phenotypes in human GBMs. Using tumortropic NSC/MSCs approved for clinical trials to deliver lipo-polymeric nanoparticle (LPNP)-encapsulated siRNA medicine to knockdown the 4 master TFs in GBM, we propose a novel in vivo strategy for effective gene therapies for heterogeneous cancers such as GBM. We hypothesize that novel non-viral gene therapies can be designed to arrest GSC fate in gliomas by suppressing the master TFs that control GSC phenotypes, and propose the following novel strategies - Strategy 1: To neutralize the GSC- promoting production of master TFs with customizable surface chemistry to achieve cell type selectivity and targeted drug delivery and validate their therapeutic efficacy in vitro against GSC models bearing personalized genomic background. Strategy 2: To pioneer stem cell-mediated in vivo LPNP delivery of siRNA targeting GSC phenotypes promoted by the master TFs while leveraging our well established model of NSC or MSCs- based therapies. Strategy 3: To enhance nanoparticle delivery to GSC via systemic circulation, we also propose to tackle the delivery of NP across the blood briar barrier. Specifically, we will examine NP-recycling by endothelial cells from both endogenous and iPSC origins, as a novel RNA-based delivery approach across the BBB. Finally, in Strategy 4: we will explore novel applications of the emerging synthetic genome editing tools, such as the transcription activator like effector nuclease (TALEN) technology and CRISPR/cas9 technology, to formulate LPNP-encapsulated delivery for genome editing tools (GETs) in order to modify the in vivo behaviors of glioblastoma stem-like cells and examine the impact on survival in animals with experimental brain tumor models.